Basic Science and Pathogenesis.

Background: Presenilin 2 (PSEN2) is one of three deterministic risk genes that increases the risk of early-onset Alzheimer's Disease. People with PSEN2 variants have increased risk of unprovoked seizures versus age-matched unaffected individuals yet few studies have interrogated the contributions of PSEN2 on seizure susceptibility. Critically, PSEN proteolytic capacity may be a novel regulator of hippocampal kainate-type glutamate receptors (KARs), with PSEN deletion reducing KAR availability and synaptic transmission in vitro (Barthet et al 2022). Kainic acid (KA) is a naturally occurring agonist for KARs that evokes sustained, severe seizures and status epilepticus (SE). We thus hypothesized PSEN2-KO mice would demonstrate reduced KA-SE latency, increased SE severity, worsened outcomes 7-days later, and have altered hippocampal KAR expression versus similarly treated WT mice.

Method: Using a repeated low-dose systemic KA administration model to evoke SE, we quantified the latency to SE and extent of SE-induced neuropathology in 3-4-month-old male and female PSEN2-KO versus WT mice (n = 10-16 mice/group/sex). GluK5, a KAR subunit, expression was colocalized in astrocytes and neurons by immunohistochemistry 7 days after KA-SE or sham to define the impacts of PSEN2 deletion and SE on hippocampal KAR expression.

Result: Regardless of sex, PSEN2-KO mice were more susceptible to KA-SE than WT mice. Male PSEN2-KO mice progressed to SE faster than WTs (78.6±25.3 versus 98.2±16.0 min; t = 2.43, p = 0.027); female PSEN2-KO mice were also more susceptible to KA-SE relative to WTs (85.3±32.2 versus 112.2±15.4 min; t = 2.45, p = 0.022). Basal GluK5 expression did not differ between sexes or genotypes. However, in male mice 7-days post-KA-SE insult GluK5 expression was significantly increased over basal levels in WT mice (p = 0.0028), but PSEN2-KO mice GluK5 levels were unchanged from basal expression (p = 0.9819). Regardless of genotype, female mice GluK5 levels were unchanged from basal expression at 7-days post-KA-SE insult, revealing sex differences in post-SE outcomes.

Conclusion: Loss of normal PSEN2 function increases susceptibility to KA-induced seizures and SE, which cannot be explained by basal GluK5 expression differences. However, increased GluK5 expression in male WT relative to PSEN2-KO mice 7-days post KA-SE, further substantiates a role of PSEN2 in KAR availability. Sex differences in GluK5 and GFAP were also apparent post-SE.